The anticonvulsive topiramate (TPM) has been successfully used as a therapeutic agent for the treatment of substance abuse, including alcohol and nicotine dependence, but the precise therapeutic mechanisms are unknown. The objective of this proposal is to determine the likely therapeutic mechanism of TPM by using event-related potential (ERP) measures, with participants recruited as part of a currently funded multisite placebo-controlled clinical trial treating alcohol-dependent smokers. As part of the parent grant, participants will be randomized to receive placebo, low-dose TPM (up to 125 mg/day), or high-dose TPM (up to 250 mg/day), along with brief behavioral compliance enhancement treatment, to prevent relapse to smoking and heavy drinking. For this proposal, participants (n=123; parent grant n=78, this proposal n=45) at The University of Texas MD Anderson Cancer Center site will complete two laboratory ERP assessments that coincide with clinical visits at baseline (1 week pre-medication, 6 weeks pre-quit) and pre-quit (5 weeks on medication, 1 week pre-quit). These assessments will consist of dense-array ERPs (129 sensors) recorded during the presentation of pictures with drug-related (alcohol and cigarette cues), emotional (pleasant and unpleasant), and neutral content. The late positive potential (LPP) ERP component will provide us with a central nervous system measure of motivational salience of the pictures. The first specific aim of this study is to identify TPM's therapeutic mechanism by evaluating its impact on the motivational salience of drug-related and emotional cues, and the second aim is to determine which therapeutic mechanism mediates the impact of TPM on post-quit drug use, reinforcement, craving, and withdrawal. The significance and impact of this project are threefold: 1) this will be the first study to evaluate the likely therapeutic mechanisms of TPM in the treatment of alcohol-dependent smokers, 2) the proposed biomarker for identifying therapeutic mechanisms, LPP ERP measures of motivational salience, could be used to identify which alcohol-dependent smokers are likely to benefit from TPM, and 3) this biomarker could be used to identify the likely therapeutic mechanisms of other pharmacological treatments of substance dependence and those who would likely benefit from them. We anticipate that our data will have a positive impact by contributing to the refinement of current models of drug addiction and will fundamentally advance our knowledge of the neurobiological processes involved in nicotine addiction. PUBLIC HEALTH RELEVANCE: This proposal will be the first to investigate the likely therapeutic mechanisms of the medication topiramate in the treatment of alcohol-dependent smokers and to identify those who would likely benefit from this promising treatment of alcohol and nicotine dependence. Understanding how this new treatment works and who would likely benefit from it could help more alcohol-dependent smokers become addiction-free.